PT  - JOURNAL ARTICLE
AU  - Julie Jacquemyn
AU  - Sabine Kuenen
AU  - Jef Swerts
AU  - Benjamin Pavie
AU  - Vinoy Vijayan
AU  - Ayse Kilic
AU  - Dries Chabot
AU  - Yu-Chun Wang
AU  - Nils Schoovaerts
AU  - Patrik Verstreken
TI  - Parkinson mutations in <em>DNAJC6</em> cause lipid defects and neurodegeneration that are rescued by Synj1
AID  - 10.1101/2022.04.27.489745
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.27.489745
4099  - http://biorxiv.org/content/early/2022/04/28/2022.04.27.489745.short
4100  - http://biorxiv.org/content/early/2022/04/28/2022.04.27.489745.full
AB  - Recent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinson’s disease, but the mechanisms are not resolved. Here, we created a new Drosophila knock-in model of DNAJC6/Auxilin and find that the pathogenic mutation causes synaptic dysfunction, neurological defects and neurodegeneration, as well as specific lipid metabolism alterations. In these mutants membrane lipids containing long-chain polyunsaturated fatty acids, including phosphatidylinositol lipid species that are key for synaptic vesicle recycling and organelle function are reduced. Overexpression of another protein mutated in Parkinson’s disease, Synaptojanin-1, known to bind and synthesize specific phosphoinositides, strongly rescues the DNAJC6/Auxilin neuronal defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinson’s disease and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival in Parkinsonism.